This invention relates to an amorphous paroxetine composition suitable as a therapeutic agent.
The selective serotonin reuptake inhibitor (SSRI) antidepressants have recently emerged as effective new treatments for patients with premature ejaculation. In general, antidepressants influence more than one neurotransmitter system and have affinity for multiple receptors. This heterogeneity of action produces mixed effects, including those on the sexual response cycle. Sexual dysfunction associated with antidepressants, including delayed and completely abolished ejaculation, has been a subject of numerous case reports, studies, and review articles [for example, J. Clin. Psychiatry 54, 209-212, (1993); J. Clin. Psychopharmacol. 3, 76-79, (1983); J. Clin. Psychiatry Mon. 10, 4-10, (1992); Depression 2, 233-240, (1994/1995)]. Because of the lack of abuse potential, relatively benign side effect profile, and fairly consistent reports of delayed ejaculation, SSRI antidepressants seem to be a safe treatment option for patients with premature ejaculation, especially in cases of failed psychological treatment.
The use of the SSRI antidepressant fluoxetine hydrochloride (Prozac(copyright)) in this regard has been described in U.S. Pat. No. 5,151,448 to Crenshaw et al. A similar treatment, at a relatively lower dosage of active ingredient, has been described in U.S. Pat. No. 5,276,042 to Crenshaw et al. for the SSRI antidepressant paroxetine hydrochloride (Paxil(copyright)). Other anti-anxiety drugs such as chlordiazepoxide (Librium(copyright)) and diazepam (Valium(copyright)) are not suitable for the treatment of premature ejaculation.
The preparation of a class of SSRI antidepressants has been disclosed in U.S. Pat. No. 4,007,196 to Christensen et al. In Example 2 of this patent, the preparation of (xe2x88x92)-trans-4R-(4xe2x80x2-fluorophenyl)-3S-[(3xe2x80x24xe2x80x2-methylenedioxy-phenoxy)methyl]-piperidine (generic name paroxetine) is described (formula A), 
wherein paroxetine is obtained as a free base then converted to its maleic acid salt. The use of the acetate salt of paroxetine has been described [Psychopharmacology 57, 151-153 (1978); Psychopharmacology 68, 229-233 (1980); European Journal of Pharmacology 47, 351-358 (1978)].
In general the hydrochloride salt of a basic compound, such as paroxetine, is preferred for therapeutic use because of its physiological acceptability. There has been limited use of the hydrochloride salt of paroxetine in aqueous solution [Acta. Pharmacol. Et Toxicol. 44, 289-295 (1979)]. U.S. Pat. No. 4,721,723 to Barnes et al. disclosed the preparation of a crystalline paroxetine hydrochloride hemihydrate in organic solvent media. However, this particular process requires considerable post-synthetic treatment of the product in order to remove the organic solvent and recrystallization procedures in order to obtain a useful purified crystalline form, which adds to the difficulty and overall cost of production. Non-crystalline, i.e., amorphous, paroxetine hydrochloride has been reported by Barnes et al. to be an undesirably hygroscopic solid of poor handling qualities for commercial use.
Some success in preparing a free-flowing, substantially non-hygroscopic solid form of amorphous paroxetine hydrochloride-ethanol composition was disclosed in U.S. Pat. No. 5,672,612 to Ronsen et al. The amorphous paroxetine hydrochloride-ethanol composition was amenable to incorporation into both tablet and suppository dosage forms, and suitable as a therapeutic agent, especially for the treatment of premature ejaculation.
However, there is still a need and desire for the preparation of solid dispersions of amorphous paroxetine hydrochloride composition substantially free of organic solvents. It has been surprisingly found that solid dispersion of amorphous paroxetine hydrochloride can be efficiently prepared from an aqueous solvent medium.
Compositions of amorphous paroxetine hydrochloride having at least one non-ionic water-soluble polymer and an acidulant compound, as well as methods for production of such compositions from an aqueous solvent-based medium are disclosed. A preferred water-soluble polymer is polyvinylpyrrolidone (PVP).
The present inventive method preferably produces substantially stable amorphous paroxetine hydrochloride solid dispersion compositions from an aqueous solution of paroxetine hydrochloride, polyvinylpyrrolidone and an acidulant followed by drying of the product. The term xe2x80x9cacidulantxe2x80x9d as used herein refers to nontoxic biocompatible organic and inorganic acids having a dissociation constant value (pKa) in the range of about 2 to about 7. Optionally, a water-miscible co-solvent capable of forming an azeotropic mixture with water can be present in the aqueous solution.
Addition of polyvinylpyrrolidone to the composition is useful in improving the stability of the amorphous paroxetine hydrochloride composition by preventing the spontaneous crystallization of the amorphous form to the crystalline form. Preferred acidulants are hydroxycarboxylic acids. A preferred hydroxycarboxylic acid is citric acid.
In a preferred method aspect, the amount of citric acid is in the range of about 1 to about 10 weight percent based on the weight of paroxetine hydrochloride, and preferably is in the amount of about 3 weight percent. The molar ratio of polyvinylpyrrolidone to paroxetine hydrochloride preferably is in the range of about 100 percent to about 300% percent. Drying can be carried out by rotary evaporation, spray drying, oven drying and the like.
A preferred amorphous paroxetine hydrochloride can be prepared according to the procedure set forth in U.S. Pat. No. 5,672,612 to Ronsen et al. and is incorporated herein by reference.
This invention beneficially provides for the efficient preparation of stable, solid dispersions of amorphous paroxetine hydrochloride compositions in an environmentally acceptable process. The inventive process avoids the inherent problems associated with the use of non-aqueous solvents and eliminates the additional steps and costs associated with preparation, of crystalline forms. The amorphous paroxetine composition embodying the present invention is well suited for the preparation of tablet dosage forms containing paroxetine.